We strive to discover genomic events that cause human cancers and infectious causes for diseases of unknown origin. We then seek to apply these discoveries to improving diagnosis and treatment for these diseases. One particular focus is lung cancer pathogenesis and targeted therapy.

Somatic genetic alterations in cancer: We use genome-scale approaches to discover chromosomal alterations and cancer-causing mutations. Our group is active in The Cancer Genome Atlas (TCGA) project to perform multi-modality analyses of human cancers, where I lead the copy number and lung cancer efforts. By analysis of somatic copy number alterations, we have defined both lineage-specific and cancer-universal regions of amplification and deletion (Beroukhim et al., 2010; Zack et al., 2013). We identified the most common DNA amplification in lung adenocarcinoma as targeting NKX2-1, a lung lineage-determining transcription factor (Weir et al., 2007) and in squamous cell lung carcinoma as targeting SOX2, also a lineage-specific transcription factor (Bass et al., 2009).

Functional analysis of lung cancer genes: We work to understand transformation by the major oncogenes that cause lung cancer, focusing on EGFR, the Ras pathway, and NKX2-1, and to apply this understanding to lung cancer therapy. We showed that distinct EGFR mutants are differentially sensitive to distinct inhibitors (Greulich et al., 2005) and have uncovered a role for EGFR dimerization in modulating susceptibility to inhibitors in lung and colorectal cancers (Cho et al., 2013; Cho et al., 2014), establishing the concept of mutant-selective therapy. We are now studying a large number of novel oncogenic mutants identified in genome sequencing screens (Imielinski et al., 2012) while actively pursuing targeted therapies in the EGFR pathway.

Discovery of pathogenic microbes: We developed a novel approach to discover microbial sequences in cryptic infectious diseases, by sequencing DNA from diseased tissues and removing sequences that match the human genome computationally, leaving microbial sequences (Weber et al., 2002; Kostic et al., 2011). We have applied these methods to uncover a pathogenic basis for the transplant-associated cord colitis syndrome (Bhatt et al, 2013). Furthermore, we have identified an enrichment of Fusobacterium nucleatum in colorectal carcinoma (Kostic et al., 2012) and have obtained evidence supporting a role for Fusobacterium in mediating intestinal carcinogenesis (Kostic et al., 2013).